Heart failure is the end-stage of cardiovascular diseases and has high death rate. Myocardial infarction and myocardial reperfusion injury are the major factors for heart failure. Although the experimental studies both in china and abroad have been revealed that calcium antagonists and free radical scavengers have effects on both treatment of myocardial infarction and protection against reperfusion injury, most calcium antagonists have limited clinical use as a result of inhibiting myocardial contraction and reducing heart function, and free radical scavengers do not have direct effect on heart function, which makes their clinical effect not fully established yet.
The therapeutic principles for heart failure are increasing heart function, vasodilating and diuretic therapy. Cardiotonics increase cardiac output by enhancing myocardial contractility to maintain the blood supply for the vital organs such as heart, brain and kidney etc. Vasodilators and diuretics decrease the load of the heart to protect heart function. However, the various cardiotonics such as cardiac glycosides, catecholamine, phosphodiesterase inhibitors (PDEI) and the like have high toxic side-effects, because they enhance the myocardial contractility mainly by increasing the concentration of intracellular calcium so as to cause proarrhythmic risk and prone to intracellular calcium overload. Although diuretics are used to be the first choice for treatment of cardiac failure, they can cause side effects such as electrolyte disturbance. Recent studies have demonstrated that angiotensin converting enzyme inhibitors (ACEI) have the effects of treating congestive heart failure and protecting cardiac muscles against ischemia and reperfusion injury, but their long term effectiveness needs to be observed.
Piperphentonamine hydrochloride (PPTA) is a novel cardiovascular chemical. The pharmacodynamic studies of PPTA demonstrated that it has good dual effects for protecting injured cardiac muscles and enhancing cardiac function with reduced myocardial oxygen consumption. PPTA increases the sensitivity of myocardial contractile proteins to Ca2+ without increasing the calcium concentration inside the myocardial cells, even antagonizing intracellular calcium overload, thus suggests that it will not have the risk for proarrhythmia. PPTA is quickly metabolized so that it will not accumulate in the body. Concluded from the above, PPTA is calcium sensitizing cardiotonic and a myocardial protector. There has been no similar drug in the world so far. The chemical structure of Levosimendan (Simdax), the first calcium sensitizing cardiotonic in the world, marketed by Orion Corporation, Finland in 2000, has totally different from PPTA's. The systemic toxicity studies showed that PPTA is low toxic and has high therapeutic index. The raw materials required to synthesize PPTA are readily available and stable for storage under normal temperature. The synthesizing process is simple and environment friendly, and the production cost is low. The dosage form of PPTA is lyophilized powder for injection.
The Chinese Application No. 02125318.8, titled “Piperphentonamine, its salts and preparation method thereof”, discloses a piperphentonamine compound, its salts and preparation method thereof, and mentions that the synthetic piperphentonamine hydrochloride has high purity and little toxic side-effect, it is promising to be developed into a novel drug for treatment of heart failure and protection against ischemia and reperfusion injury.
The Chinese Application No. 02125316.1, titled “The use of piperphentonamine and salts thereof in the preparation of a medication for treatment cardiovascular diseases”, disclosed that piperphentonamine or its pharmaceutical acceptable salts can be formulated into solution, powder, tablet or capsule for intravenous injection, muscle injection and oral administration respectively, with a dosage from 0.1 to 1.0 mg/kg. But both the above patents have not described a composition and a preparation method of the piperphentonamine hydrochloride lyophilized powder for injection in detail, nor the use thereof.
The Chinese Applicaion No. 03141625.X discloses metadoxin lyophilized powder for injection and preparation method thereof. A multistage freeze-drying method for drug solution during lyophilizing process is employed, which comprises keeping the lowest temperature at −30 to −70° C. for 2 to 10 hours and rising the temperature ramped up to the highest point 0 to 70° C., keeping it for 1 to 15 hours. The temperature difference between the lowest and the highest point for freeze-drying is large and hard to control, and also makes a strict requirement for freeze-drying equipments.